Apolipoprotein E genotype in Spanish patients of Alzheimer's or Parkinson's disease

Apolipoprotein E genotype in Spanish patients of Alzheimer's or Parkinson's disease

JOURNAL OF TM NEUROLOGICAL SCIENCES Journal of the Neurological Sciences 134 (1995) 146-149 ELSEVIER Apolipoprotein E genotype in Spanish patient...

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JOURNAL

OF TM

NEUROLOGICAL SCIENCES Journal of the Neurological Sciences 134 (1995) 146-149

ELSEVIER

Apolipoprotein

E genotype in Spanish patients of Alzheimer’s or Parkinson’s disease

Dolores Ibarreta a, Teresa G6mez-Isla b, Albert0 Portera-SBnchez b, Roberto Parrilla a, Matilde S. Ayuso a,* a Department

of Human

Physiology and Molecular Genetics, Centro b Department of Neurology, Hospital

de Investigaciones Biol6gicas (CSIC), Velkzquez Universitario Dote de Octubre, Madrid, Spain

144, E-28006

Madrid,

Spain

Received 14 March 1995; revised 29 June 1995; accepted 14 July 1995

Abstract Blood donors of the Madrid area show a 6% frequency of apolipoprotein E genotype carrying allele ~4. This frequency is smaller than other populations of Caucasian origin. This proportion decreases to 4% in a selected sample of healthy individuals of ages > 60 years. The frequency (34%) of the allele ~4 was significantly increased in patients of late onset Alzheimer’s disease, similarly to other populations. An earlier age of onset of the dementia is observed in the patients of late-onset Alzheimer’s disease carrying the allele ~4. No increased frequency in allele ~4 frequency was found in patients of early-onset Alzheimer’s disease. Patients of Parkinson’s disease do not show any differences in the frequency of the alleles of apolipoprotein E when compared with healthy individuals. Keywords:

Alzheimer’s disease; Parkinson’s disease; Apolipoprotein E

1. Introduction The presence of apolipoprotein E (ApoE) in the amyloid deposits and neurofibrillary tangles of late-onset Alzheimer disease (AD) patients is well documented (Wisniewski and Frangione, 1991; Namba et al., 1991; Schmechel et al., 1993). There are three common variants of ApoE in most human populations, ApoE ~2, ApoE ~3 and ApoE ~4. They differ in amino acid substitutions at one of two positions of the protein (Mahley, 1988). The high frequency of one of these variants, the ApoE ~4, in patients of late-onset AD (Corder et al., 1993; Saunders et al., 1993), suggested its possible implication as a risk factor of the disease.

The role of ApoE in the pathogenesisof the AD has been based on the capacity of ApoE ~3 and ApoE ~4 of forming monofibrillar structures with the P-amyloid pep-

et al., 1994) has originated some doubts on the specificity of the role of ApoE on the pathogenesisof AD. Furthermore, an associationbetween cognitive decline and ApoE ~4 allele has been found in a general population of elderly men (Feskens

et al., 1994).

In order to evaluate the involvement of apoE isoforms in senile diseasesof the Madrid area, we have determined the apoE

genotypes

of patients

with

AD

and compared

these genotypes with those of age-matched controls. The associationof neurofibrillary pathology with the frequency of the ApoE ~4 allele (Hansen et al., 1994) and the recent observation (Galasko et al., 1994) that there is an overrepresentation of apoE ~4 allele in the Lewy body variant of AD (Hansen et al., 1990) led us to include in this study a group of patients with Parkinson’s disease (PD). PD pathology is characterized by the occurrence of Lewy

bodies and also by neurofibrillary tangles, similar to those

tide, being ApoE ~4 more efficient than ApoE ~3 (Sanan et al., 1994). Recently, the observation that senile dementias other than AD are also accompanied by a high fre-

observed

quency of ~4 allele of ApoE (Noguchi et al., 1993; Betard

2. Materials and methods

* Corresponding author. At: CIB, Veltiquez Spain. Fax/Phone: (+34-l) 562 8025.

A total number of 71 patients (26 men, 45 women) of agesranging from 52 to 92 years (average 69.5 + 1 years) were diagnosed in the Department of Neurology of the

0022-510X/95/$09.50 SSDI 0022-510X(95)00238-3

144, E-28006 Madrid,

Q 1995 Elsevier Science B.V. AI1 rights reserved

in AD (Hakim

and Mathieson,

1979).

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et al. /Journal

of the Neurological

Hospital Universitario Dote de Octubre (Madrid, Spain) as probable AD according to the NINCDS-ADRDA criteria (McKahnn et al., 1984). At the time of the study, patients had an average of 3.5 f 0.3 years of disease progression. The degree of dementia was assessed by the mini-mental test (Folstein et al., 1975), with values ranging from 0 to 23 points (average 8.4 f 1.2). Fifty patients had no family history of dementia, while 21 had a positive familial history. PD patients (n = 64, ages 44-90; 65.8 k 16 years) diagnosed according to the criteria of the Parkinson Study Group (1989), were also included in the study. Dementia was excluded by the mini-mental test and complete neurological examination. Two groups of controls were selected. One of 186 blood donors (50% males and 50% females, aged 18-63, 36 f 1.4 years) and a second group of 42 healthy age-matched older individuals, without any clinical symptom of AD or PD (52-90 years of age; 67.7 f 1.91. DNA was obtained from peripheral blood specimens. Restriction analysis of the PCR-amplified ApoE DNA fragments was carried out as previously described (Wenham et al., 1991). Allele frequencies for patients with AD or PD and control subjects were estimated by counting alleles and calculating sample proportions. Frequencies of ApoE genotypes in patients and control subjects were compared using the Student’s r-test. Values are means f SEM.

3. Results and discussion Table 1 depicts the frequencies of ApoE alleles in the first freely selected control group of blood donors and in the healthy age matched controls. The allele ~4 in blood donors controls (6%) was found to be less frequent than previously described in other groups of Caucasian origin (lo-16%) (Mayeux et al., 1993; Houlden et al., 1993; Saunders et al., 1993) and similar to healthy French centenarians (5.2%) (Schachter et al., 1994). It is also similar to

Table ApoE

1 allele frequencies

Population

Abbreuiations: a Statistically

134 (1995)

147

146-149

normal Japanese population (6-9.5%) which seems to have a lower morbidity from AD (Ueki et al., 1993; Kawamata et al., 1994; Yoshizawa et al., 1994; Okuizumi et al., 1994). This wide variation of the frequency of allele ~4 has been noticed before, but within different ethnic groups (Utermann, 1994). Since the Spanish population does not seem to have a lower prevalence of AD than other communities of Caucasian origin (Rocca et al., 19911, other factors, besides the frequency of allele ~4, may be important in the development of the disease. The frequency of ~2 and ~4 alleles was found to be lower and that of ~3 allele higher in the age matched controls than in the randomly selected control population, although the differences were not statistically significant. The AD patients show, in agreement with observations made in other populations (Strittmatter et al., 1993; Ueki et al., 1993; Anwar et al., 1993; Poirier et al., 1993; Brousseau et al., 1994; Lehtimlki et al., 19951, a statistically significant higher frequency of ~4 allele, and a lower frequency of ~3 than the general population or age-matched controls. The allele distribution of the early-onset patients (EOAD < 65 years) does not show any statistically significant difference from the general population controls. This is in agreement with previous reports describing the allele distribution in other populations (Saunders et al., 1993; Kawamata et al., 19941, but in contrast with other reports (Dai et al., 1994; Okuizumi et al., 1994; Van Duijn et al., 1994; Yoshizawa et al., 1994; Lehtovirta et al., 1995). The ApoE ~4 allele was present in 34% of the late-onset patients (LOAD > 65 years), a proportion similar to those previously described (Strittmatter et al., 1993; Ueki et al., 1993; Anwar et al., 1993; Poirier et al., 1993; Brousseau et al., 1994; LehtimIki et al., 1995). This proportion increased to 50% when only LOAD patients with familial history of dementia (FLOAD) were considered. No differences of ~2 allele were found between AD and the age matched control group, neither between sporadic and familial cases (Table 1). These observations do

in AD and PD No. of alleles

Blood donors Age-matched controls AD EOAD LOAD FLOAD SLOAD PD > 65 years < 65 years

Sciences

372 84 130 36 94 22 66 128 66 62

Allele

frequencies

E2

E3

0.06 + 0.01 0.05 + 0.02 0.06 + 0.02 0.03 + 0.001 0.06 + 0.001 0.09 f 0.004 0.06~0.001 0.09 & 0.026 0.11*0.040 0.05 f 0.001

0.88 * 0.92 f 0.67 f 0.89 f 0.60 f 0.41+ 0.63 f 0.86 f 0.86 + 0.89 f

EOAD = early onset AD; LOAD = late onset AD; FLOAD = familial significant difference between AD and the other groups, p < 0.05.

late onset AD;

E4 0.02 0.03 0.04 0.003 0.002 0.011 0.004 0.031 0.05 0.002

0.06 0.04 0.27 0.08 0.34 0.50 0.32 0.05 0.04 0.06

a a a a

SLOAD

= sporadic

+ 0.01 + 0.02 f 0.04 f 0.002 + 0.002 + 0.011 rt 0.003 * 0.019 + 0.025 If: 0.001

late onset AD.

a a a a

148

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of the Neurological

Sciences 134 (1995)

146-149

age of onset. Genotypes of ApoE in PD patients were also evaluated, but no statistical difference from the controls could be found. c3

ApoE AtIdes 2+3 ApoE Allele 4

70

74

78

X2

X6

90

Age (years) Fig. 1. ApoE alleles and age of onset of LOAD.

not support the protective effect of allele ~2 previously suggested (Corder et al., 1994; Chartier-Harlin et al., 1994; Talbot et al., 1994; Rubinsztein et al., 1994). Table 1 also shows that the frequencies of ApoE alleles in non-demented PD patients (n = 64) were similar to the controls and that the genotype of PD does not depend upon the age of onset of the disease. Thus, none of the ApoE isoforms seems to be an important risk factor against this disease. This observation agrees with the recent studies of Marder et al. (1994) and Rubinsztein et al. (1994) on elderly PD patients which found that ApoE allele frequencies in PD did not differ from controls. We could not find any association between the age of onset of PD and ApoE genotype. The frequency of each allele was compared to that of the corresponding Hardy-Weinberg (HW) theoretical distribution. All groups were in HW equilibrium, indicating that the homozygous .54/~4 genotype does not confer more susceptibility to AD than the heterozygous &4/.53 genotype. The possible relationship between the ApoE genotype and the age of onset of AD is shown in Fig. 1. The EOAD patients (less than 65 years old) carry mainly the ApoE alleles ~2 and ~3. The group of LOAD patients (over 65 years) shows a greater number of cases carrying ~4 allele. Within the latter group, the maximum incidence of ApoE ~4 allele appears at 70-72 years, while ~2 + 3 alleles occurred at 78 years of age. These observations agree with previous studies (Corder et al., 1993; Payami et al., 1994; Lehtovirta et al., 1995) in which ~4 allele appeared to be associated with an earlier age of onset of the late-onset AD. In summary, the frequency of the ApoE ~4 allele in the Spanish population from the Madrid area is lower than in other populations of Caucasian origin. As in other populations the frequency of the ApoE ~4 allele is higher in LOAD patients, particularly in those with familial history of dementia, but not in EOAD patients. The presence of the ApoE ~4 allele in LOAD is accompanied by an earlier

Acknowledgements We are grateful to Professor T. Saitoh from the University of California for his helpful suggestions and Dr. E. Torroja for his advise in performing the statistical evaluation of the data. This work was supported by grants from Direcci6n General de Investigaci6n Cientifica y TCcnica (PB93-01631, Plan National de Investigacidn Cientifica y TCcnica (SAL509/91), Comunidad Aut6noma de Madrid (142/92) and Fondo de Investigaciones Sanitarias (93/0162). Dolores Ibarreta was recipient of a predoctoral fellowship from the Spanish Ministry of Education and Science (FPI/91).

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